Quinazoline-4-amino-2-(piperidine-1-yl-4-substituted) derivatives having antihypertensive activity, a method for their preparation and their pharmaceutical use

ABSTRACT

New quinazolines are described of general formula (I), in which Ar is an unsubstituted phenyl group or a phenyl group mono-substituted with a methoxy, ethoxy or methyl group; an unsubstituted pyridyl group (2-, 3- or 4-yl) or a pyridyl group mono-substituted with a methoxy or methyl group; an unsubstituted furyl group (2- or 3-yl) or a furyl group substituted with a methoxy or methyl group; a benzofuryl group (2- or 3-yl); an indolyl group (2- or 3-yl); a thiophenyl group (2- or 3-yl); a naphthyl group (1- or 2-yl) and their salts obtained from pharmaceutically acceptable inorganic or organic acids. These new quinazolines are useful in the treatment of hypertension, congestive heart failure, prostate hypertrophy, various urinary tract disorders and pathological symptoms caused by hyperactivity or disfunctioning of the noradrenergic neural system. ##STR1##

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to 2-piperidine (4-substituted)derivatives of 4-amino-6,7-dimethoxyquinazolines. These compounds areuseful in the treatment of hypertension, congestive heart failure,prostate hypertrophy, various urinary tract disorders and pathologicalsymptoms caused by hyperactivity or dysfunctioning of the noradrenergicneural system.

2. Description of the Related Art

The hypotensive activity of a variety of quinazoline-piperazinederivatives is well known. For example, U.S. Pat. No. 3,511,836describes the hypotensive activity of4-amino-6,7-dialkoxy-2-(piperazine-(4-substituted)-1-yl)quinazolines, inwhich the substituent in the 4-position of the piperazine is a benzoylor furyl group; U.S. Pat. No. 4,001,237 describes the hypotensiveactivity of analogous derivatives in which the 4-substituent is anoxazolyl, thiazolyl, isoxazolyl or isothiazolyl group; U.S. Pat. No.4,188,390 describes the hypotensive activity of analogous derivatives inwhich the 4-substituent is, inter alia, a group such as1,4-benzodioxan-2-carbonyl.

BRIEF SUMMARY OF THE INVENTION

The subject of the invention is new 2-piperidine(4-substituted)derivatives of 4-amino-6,7-dimethoxy-quinazoline which may berepresented by the general formula (I) indicated below ##STR2## inwhich: Ar is

an unsubstituted phenyl group or a phenyl group mono-substituted with amethoxy, ethoxy or methyl group

an unsubstituted pyridyl group (2-, 3- or 4-yl) or a pyridyl groupmono-substituted with a methoxy or methyl group

an unsubstituted furyl group (2- or 3-yl) or a furyl group substitutedwith a methoxy or methyl group

a benzofuryl group (2- or 3-yl)

an indolyl group (2- or 3-yl)

a thiophenyl group (2- or 3-yl)

a naphthyl group (1- or 2-yl)

The compounds of the present invention have been shown to be powerfulantagonists to noradrenergic receptors (alpha_(1A) and alpha_(1B)receptor subtypes) and serotonergic receptors, and can therefore be usedto advantage in treating various human illnesses, whether at the levelof the cardiovascular system, in particular for treating hypertension,as well as in the urogenital apparatus, for example, in the treatment ofprostate hypertrophy, various urinary tract problems and, in general,the pathological manifestations caused by hyperactive or disfunctioningadrenergic receptors.

DETAILED DESCRIPTION OF THE INVENTION

One of the advantages of the new piperidine-quinazoline derivatives ofthe invention over previously known piperazine-quinazoline compoundshaving hypotensive activity is that, as they do not contain thepiperazine nucleus in their chemical structure, their use shouldeliminate the potential danger of neurotoxic manifestations in patientswith renal failure or central nervous system disorders.

A further advantage is the absence from their chemical structure of thecarbonyl-piperazine bond which is susceptible to in vivo enzymatichydrolysis. In effect, compounds with a high bioavailability andduration of action are obtained. This allows the therapeutic dose to bereduced, for a given effectiveness and, consequently, any undesirableside-effects will be reduced.

In addition to the powerful hypotensive effect demonstrated by thecompounds of the invention linked to the blocking of the alpha₁adrenergic receptor, they can also display an antagonistic effect onseratonin receptors which are widely present in some peripheral tissuessuch as the vascular musculature and the thrombocytes, thereby alsoblocking the amplification effect of seratonin on the vasoconstrictiveand thrombocytic-aggregation activity of catecholamines.

Pharmaceutical forms of the compounds of the invention may be preparedby conventional techniques in the form of, for example, tablets,capsules, suspensions, solutions, suppositories or patches, and may beadministered orally, parenterally, rectally or transdermally, or inother suitable ways to obtain the therapeutic effect such as, forexample, as solid preparations for oral use having a protracted actionwhich allow the controlled release of the active ingredient over time.

The active ingredient is usually administered to the patient in areference dose which may vary from 0.001 to 1 mg/kg bodyweight per dose.In the case of parenteral administration it is preferable to use ahydrosoluble salt of the compound in question such as the hydrochlorideor another non-toxic, pharmaceutically acceptable salt. The inactiveingredients may be substances that are commonly used in pharmaceuticalpreparations such as excipients, binders, aromatisers, dispersents,colorants, humectants etc.

The method for the preparation of the derivatives of the invention (I)consists of reacting the piperidine derivatives of the formula (II):##STR3## in which Ar has the meaning indicated above, with2-Cl-4-amino-6,7-dimethoxy quinazoline in a solvent with a high boilingpoint, preferably isoamyl alcohol, in the presence or absence of aninert tertiary base which acts as a proton acceptor, at a temperature of70-150° C. for a period of 1-48 hours, and isolating the compounds offormula (I) from the reaction medium by filtration, preferably in theform of the hydrochloride.

The intermediate piperidines of formula (II) used in the presentinvention, some of which are compounds which are already known, wereprepared in a similar manner to that described in U.S. Pat. No. 2891066.This method consists of a series of reactions comprising:

a) reacting the aromatic aldehydes Ar--CHO, in which Ar has the meaninggiven above, with ethyl acetoacetate to give the compound of formula(III): ##STR4## b) hydrolysing the compound of formula (III) with NaOHto give the glutaric derivative of formula (IV): ##STR5## c) treating(IV) with excess ammonia at high temperature to give the imides offormula (V): ##STR6## d) reducing the imides (V) with LiAlH₄ to give thedesired piperidines of formula (II).

The following examples are given to illustrate the invention better.

EXAMPLE 1 Preparation of 4-(2-pyridyl)-bis-ethyl acetoacetate

(Compound A of Formula III)

30 ml of ethanol, 50 ml of 2-pyridylcarboxyaldehyde (0.5256 moles), 133ml of ethyl acetoacetate (1.0513 moles) and 10.4 ml of piperidine(0.1051 moles) were mixed in sequence.

At the end of the addition, the reaction was allowed to proceed underagitation at 35-40° C. for 8 hours. The solvents and the reactants wereevaporated under vacuum, 166 g of a dark, non-friable oily residue beingobtained.

Formula: C₁₈ H₂₃ NO₆. Yield: 0.475 moles (90%)

TLC: Rf 0.20 (toluene/AcOEt 7:3).

The compound was used without further purification in the next reaction.

EXAMPLE 2 Preparation of 3-(2-pyridyl)glutaric acid (hydrochloride)

(Compound B of Formula IV)

166 g of Compound A (Example 1) (0.475 moles) were added dropwise to asolution containing 800 ml of ethanol and 290 g of 65% NaOH in H₂ O(4.7303 moles). At the end of the dropwise addition the reaction wasallowed to proceed at boiling point for approximately 2 hours. Aftercooling, the paste-like residue formed was taken up with 400 ml ofisopropyl alcohol and filtered. The solid was dissolved in 500 ml H₂ Oand, after cooling, the solution obtained was acidified with 37% HCl.The acidic solution was evaporated to dryness under vacuum, the residuewas taken up in methanol and the solid precipitate (NaCl) was discarded.The methanolic solution was evaporated to dryness and gave 74 g of adense, non-friable oil which was used as such in the next step.

Formula: C₁₀ H₁₁ NO₄.HCl. Yield: 0.301 moles (63%)

TLC: Rf 0.49 (n-BuOH/acetic A./H₂ O 5:2:2).

EXAMPLE 3 Preparation of 3-(2-pyridyl)-glutarimide

(Compound C of Formula V)

70 g of 3-(2-pyridyl)glutaric acid hydrochloride (Compound B) (0.2489moles) were dissolved in 80 ml of 28% ammonia (1.1398 moles). This washeated under agitation to 80° C., when most of the excess ammoniaevaporated. The H₂ O also evaporated when the temperature reached100-110° C. The resulting semi-solid viscous mass was then heated to180° C. at which point the ammonia was completely eliminated. Once theevolution of ammonia ceased, the reaction mixture was cooled and theresidue was taken up in ethyl acetate and was washed with NaHCO₃ toremove unreacted (B). The organic phase was then washed with water,dried and evaporated. The solid residue obtained was taken up inisopropyl ether and filtered. 32 g of product (C) were obtained afterdessication.

Formula: C₁₀ H₁₀ N₂ O₂. Yield: 0.1682 moles (59%)

TLC: Rf 0.62 (MeOH/AcOEt 9:1)

Melting point: 126-127° C.

EXAMPLE 4 Preparation of 4-(2-pyridyl)-piperidine

(Compound D of Formula II)

25 g of LiAlH₄ (0.63 moles) were suspended in 600 ml anhydroustetrahydrofuran (THF). The suspension was heated to 40° C. and, at thistemperature, 30 g of 3-(2-piridyl)-glutarimide (Compound C) (0.1578moles) were added gradually.

The mixture was heated under reflux for 12 hours. It was then cooled to-10° C. and, still under cooling, was hydrolysed by the sequentialaddition of 25 ml H₂ O, 25 ml 30% NaOH and 50 ml of H₂ O. The mixturewas left to rest for several hours and then the salts were filtered offand the THF solution evaporated to dryness under vacuum. The oilyresidue was dissolved in ether and converted to the hydrochloride bytreatment with gaseous HCl. After dessication, 26 g of a pale pink solidwas obtained (Compound D) which, being hygroscopic, was used as soon aspossible.

Formula: C₁₀ H₁₄ N₂.2HCl. Yield: 0.11 moles (70%)

TLC: Rf 0.19 (n-BuOH/acetic A./H₂ O 5:2:2)

Melting point 252-255° C.

EXAMPLE 5 Preparation of1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-pyridyl)piperidine(hydrochloride)

(Compound 7 of Table 1)

20 g of 4-(2-pyridyl)-piperidine.2HCl (Compound D) (0.085 moles) weredissolved in 100 ml of H₂ O. The solution was made alkaline with 50 mlof 2N NaOH and extracted by washing with two lots of 100 ml of ethylacetate. The organic phases were pooled and evaporated to dryness, theoily residue was taken up in 300 ml of isoamyl alcohol to which wereadded 20.4 g of 2-chloro-4-amino-6,7-dimethoxy-quinazoline (0.085moles). The mixture was heated to boiling point for 5 hours and, aftercooling, the precipitate formed was filtered off and washed withacetone. 24 g of Compound 7 were obtained after drying.

Formula: C₂₀ H₂₃ N₅ O₂.HCl. Yield: 0.06 moles (71%)

TLC: Rf 0.35 (n-BuOH/acetic A./H₂ O 5:2:2)

HPLC: (r.t.) 23.8 min (see note 2 of Table 1)

Melting point: 275.7° C. (as DSC)

All of the compounds of formula (I) were synthesised by the proceduredescribed in Example 5, that is, by reacting2-chloro-4-amino-6,7-dimethoxy-quinazoline with the appropriatepiperidine of formula (II). Table 1, below, gives several derivatives offormula (I) according the invention obtained in this way together withsome identifying physico-chemical characteristics, without this beinglimiting in any way of the spirit and scope of the invention itself.

                  TABLE 1                                                         ______________________________________                                        Compounds of formula (I)                                                                                     (I)                                            1 #STR7##                                                                                                         HPLC.sup.2                                                                          DSC.sup.3                           Com-                           TLC.sup.1                                                                          (r.t) onset                               pound Formula      Ar          (r.f)                                                                              min   (° C.)                       ______________________________________                                        1     C.sub.21 H.sub.24 N.sub.4 O.sub.2.HCl                                                      Phenyl      0.71 12.3  291.9                               2     C.sub.22 H.sub.26 N.sub.4 O.sub.3.HCl                                                      2-methoxyphenyl                                                                           0.74 14.8  297.3                               3     C.sub.22 H.sub.28 N.sub.4 O.sub.3.HCl                                                      2-ethoxyphenyl                                                                            0.78 15.6  299.6                               4     C.sub.19 H.sub.22 N.sub.4 O.sub.2.HCl                                                      2-furyl     0.82 10.1  287.3                               5     C.sub.20 H.sub.24 N.sub.4 O.sub.3.HCl                                                      2-(5-methylfuryl)                                                                         0.80 12.2  274.1                               6     C.sub.19 H.sub.22 N.sub.4 O.sub.2 S.HCl                                                    2-thiophenyl                                                                              0.71 11.7  291.5                               7     C.sub.20 H.sub.23 N.sub.5 O.sub.2.HCl                                                      2-pyridyl   0.35 23.8  275.7                               8     C.sub.23 H.sub.24 N.sub.4 O.sub.3.HCl                                                      2-benzofuryl                                                                              0.78 14.5  286.3                               9     C.sub.23 H.sub.25 N.sub.5 O.sub.2.HCl                                                      2-indolyl   0.73 9.4   258.5                               10    C.sub.25 H.sub.26 N.sub.4 O.sub.2.HCl                                                      1-naphthyl  0.77 17.3  311.9                               ______________________________________                                         Note:                                                                         .sup.(1) : Eluent: nBuOH/Acetic A./H.sub.2 O(5/2/2:v/v)                       .sup.(2) : Mobile phase: phosphate buffer + MeOH(25/75)/Acetonitrile          (80/20:v/v)                                                                   Stationary phase: Adsorbosphere C18                                           .sup.(3) : DSC = Differential calorimetric scan                          

Table 2 gives some physico-chemical characteristics of the intermediatecompounds of formula (II) obtained as previously described while, forthose compounds already known, the respective "Chemical AbstractRegistry Number" is also noted.

                  TABLE 2                                                         ______________________________________                                        Compounds of formula (II)                                                                                   (II)                                            2 #STR8##                                                                                            Melting  TLC.sup.1                                                                          Registry                                 Compound   Formula     Point    (r.f)                                                                              Number                                   ______________________________________                                        4-(2-pyridyl)-                                                                           C.sub.10 H.sub.14 N.sub.2.2HCl                                                            252-255  0.19 30532-37-7                               piperidine.2HCl.sup.(2)                                                       4-phenyl-  C.sub.11 H.sub.15 N.HCl                                                                   286-287  0.64 771-99-3                                 piperidine                                                                    4-(2-methoxy-                                                                            C.sub.12 H.sub.17 NO.HCl                                                                  258-260  0.71 58333-75-8                               phenyl)-                                                                      piperidine                                                                    4-(2-ethoxyphenyl)-                                                                      C.sub.13 H.sub.19 NO.HCl                                                                  250      0.80 100617-80-9                              piperidine                                                                    4-(2-furyl)piperidine                                                                    C.sub.9 H.sub.13 NO.HCl                                                                   151-152  0.64 --                                       4-(2-furyl-5methyl)-                                                                     C.sub.10 H.sub.15 NO                                                                      --       0.71 --                                       piperidine.sup.(3)                                                            4-(2-thiophenyl)-                                                                        C.sub.9 H.sub.13 NS                                                                       --       0.52 --                                       piperidine.sup.(3)                                                            4-(2-benzofuryl)-                                                                        C.sub.13 H.sub.15 NO.HCl                                                                  235-236  0.56 54477-05-3                               piperidine                                                                    4-(3-indolyl)-                                                                           C.sub.13 H.sub.16 N.sub.2                                                                 224-226  0.55 17403-09-7                               piperidine.sup.(4)                                                            4-(2-naphthyl)-                                                                          C.sub.15 H.sub.17 N.HCl                                                                   329.sup.(5)                                                                            0.62 --                                       piperidine                                                                    ______________________________________                                         Note:                                                                         .sup.(1) : Eluent: nBuOH/Acetic A./H.sub.2 O(5/2/2:v/v)                       .sup.(2) : See Example 4                                                      .sup.(3) : Utilized directly as bases and not isolated                        .sup.(4) : Prepared in a similar way to DE3026365A                            .sup.(5) : DSC onset                                                     

DESCRIPTION OF THE PHARMACOLOGICAL ACTIVITY

1) In Vitro Anti-adrenergic Activity (Alpha₁ -antagonist)

In order to evaluate the affinity of the compounds of the inventiontowards the different alpha₁ adrenergic receptor subtypes, bindingstudies were made with the use of [³ H]-prazosin as a marked binder andrat submaxillary glands (GSM) as a tissue providing the alpha_(1A)adrenergic receptor component, rat liver as the tissue providing thealpha_(1B) adrenergic receptor component, and the human prostate as thetissue providing a mixed alpha_(1A) and alpha_(1C) component. It should,however, be noted that there is still some controversy relating to theclassification of this receptor subtype which has, moreover, alreadybeen cloned [see, for example, Pimoule et al. Eur. J. Pharmacol. 290(1995), 49-53, and Yamada et al., Life Sci. 54 (1994), 1845-1854].

a) In order to evaluate the binding of [³ H]-prazosin in the rat GSM,the method of Michel et al (Br.J. Pharmacol.) 88 (1989), 883-889, wasused with slight modifications. Two symmetrical rat glands were used soas to obtain a final pellet having a proteinaceous concentration ofapproximately 400 μg/250 μl. The experimental conditions were: specificactivity of the tracer: 74.4 Ci/mmole; incubation time 45 min (25° C.)TRIS+EDTA buffer pH 7.4.

b) In order in to evaluate the binding of [³ H]-prazosin in the ratliver, Michel's previously cited method was used with the sameexperimental binding conditions. A final pellet having a proteinaceousconcentration of approximately 600 μg/250 μl was used.

c) In order to evaluate the binding of [³ H]-prazosin in the humanprostate, the method of Yamada et al was used (Life Sci.) 50 (1992),127-135, with slight modifications. A final pellet having aproteinaceous concentration of approximately 350-400 μg/250 μl wasobtained. Incubation time 30 min (25° C.); Tris+MgCl₂ buffer pH 7.5.

The results obtained with several of the compounds of the invention arelisted in Table 3 which gives the IC₅₀ values, that is, theconcentration (in nanomoles/liter) of antagonist capable of displacing50% of the [³ H]-prazosin from the receptor.

                  TABLE 3                                                         ______________________________________                                        Inhibition of the binding of [.sup.3 H]-prazosin                              (IC.sub.50 × 10.sup.-9 M) in:                                           rat submaxiliary glands (GSM) (alpha.sub.1A receptor                          subtype)                                                                      rat liver (alpha.sub.1B receptor subtype)                                     human prostate (alpha.sub.1A + alpha.sub.1C receptor subtype)                                                human prostate                                         rat GSM     rat liver  (alpha.sub.1A + alpha.sub.1C)                  Compound                                                                              alpha.sub.1A subtype                                                                      alpha.sub.1B subtype                                                                     subtype                                        ______________________________________                                         1      6.1         13.0       2.0                                             2      18.8        7.7        7.8                                             3      10.7        14.0       10.8                                            4      3.1         1.7        3.8                                             5      3.5         2.1        1.7                                             6      4.1         6.0        4.5                                             7      3.1         8.2        5.0                                             8      18.4        5.2        20                                              9      5.7         2.9        2.5                                            10      88.0        62.0       IN (>100)                                      Prazosin                                                                              3.9         3.3        2.3                                            WB-4101 16.5        12.0       NT                                             Ketanserine                                                                           48.2        29.9       270                                            ______________________________________                                         NT: Not tested                                                           

From the data given in Table 3 it can be seen that many of the compoundsof the invention are powerful antagonists of the alpha_(1A), alpha_(1B)and alpha_(1C) adrenergic receptor subtypes. For example, the compounds4, 5, 7 and 9 generally display an activity similar to that of prazosin,while the other two reference compounds chosen, WB-4101 [J. Med. Chem.12, (1969), p. 326], a powerful alpha_(1A) antagonist, and ketanserine,a powerful 5-HT₂ and alpha₁ adrenergic antagonist, this latter beingused like prazosin in treating human hypertension, are on averageapproximately 10 to 30 times less powerful.

2) In Vitro Anti-serotinin Activity: Rabbit Aorta

The antagonist activity of some of the compounds of the invention on thecontractile activity of seratonin on isolated rabbit aorta, effectedprincipally by way of the 5-HT₂ receptors, is reported here by way ofexample. The method of Feniuk et al [Br. J. Pharmacol. (1985), 86,697-704] was used, with slight modifications. Four rings formed fromrabbit aorta were joined together to form a chain; the preparation wasplaced in an isolated organ bath in the presence of Krebs at 37° C. andattached to an isometric transducer, a tension of 2 g being applied andoxygenation was carried out continuously with O₂ --CO₂ (95-5 v/v). Aseratonin concentration(0.3 μM) was used that was capable of causingsub-maximal contraction of the preparation. The compound to be testedwas administered 10 minutes before stimulation by the agonist; use ofdifferent concentrations of the drug enabled the determination of theIC₅₀ value, that is the concentration in μg/ml of drug capable ofantagonising the contraction caused by the agonist by 50%. The resultsobtained in this way are given in Table 4 below which, for several ofthe compounds of the invention gives IC₅₀ values calculated by theregression method on a set of at least 2 experiments at 5 differentconcentrations for each of the compounds examined, these being comparedwith values obtained for several reference compounds.

                  TABLE 4                                                         ______________________________________                                        Inhibitory effect (IC.sub.50 μg/ml) on the                                 contraction caused by 0.3 μM seratonin in the                              smooth vasal musculature of isolated rabbit aorta                                                    (basal limits - p < 0.05)                              Compound    IC.sub.50  (μg/ml)                                             ______________________________________                                         1          6.0        (4.6-7.8)                                               2          14.7        (9.5-22.6)                                             3          30.0       (17.2-52.5)                                             4          11.6        (5.6-23.9)                                             5          3.1        (2.2-4.1)                                               6          32.7       (25.4-42.1)                                             7          20.0       (10.8-37.4)                                             8          6.7         (4.3-10.4)                                             9          13.0        (8.4-19.9)                                            10          inactive (>50)                                                    Prazosin    inactive (>50)                                                    WB-4101     inactive (>50)                                                    Ketanserine 0.09       (0.07-0.12)                                            ______________________________________                                    

From the data given in Table 4 it can be seen that several of thecompounds of the invention, in addition to their extremely powerfulanti-adrenergic (alpha₁) activity previously described, also show strong5-HT₂ -antagonist activity. For example, Compound 5 has an IC₅₀ of 3.1μg /ml (7.6 μM), which is approximately 30 times less than that of anextremely powerful and specific antagonist such as ketanserine (IC₅₀0.09 μg/ml). The other reference adrenergic antagonists examined such asprazosin and WB-4101 are found to be inactive until higher doses (50μg/ml) are used.

3) Hypotensive Activity in the Anaesthetised Normotensive Rat

In order to evaluate the in vivo activity, some of the compounds of theinvention were administered (IV) in bolus form to the normotensive ratanaesthetised with urethane plus ketamine. The compounds wereadministered in at least three doses in experiments performed induplicate so as to enable the calculation of ED₃₀ values, that is, thedose in mg/kg that reduces the mean basal arterial pressure by 30%. Thecompounds of the invention, and several reference standards, weredissolved in dilute hydrochloric acid at a physiologically acceptablepH, and physiological solution was administered in a volume of 3 ml/kg.Evaluations were made at two time periods, that is, the intervals 0-30min and 30-60 min after administration. The values obtained in this wayare given in Table 5 below.

                  TABLE 5                                                         ______________________________________                                        Reduction in mean arterial pressure (ED.sub.30 mg/kg)                         in the anaesthetised normotensive rat, caused                                 by the IV administration in bolus form of the                                 indicated compounds of the invention                                                         Interval Interval                                              Compound       0-30 min 30-60 min                                             ______________________________________                                         1             0.19     0.31                                                   2             0.50     0.55                                                   3             0.32     0.35                                                   4             0.08     0.10                                                   5             0.03     0.03                                                   6             0.06     0.08                                                   7             0.08     0.09                                                   8             0.07     0.09                                                   9             0.10     0.19                                                  10             1.00     1.83                                                  Prazosin       0.02     0.05                                                  WB-4101        0.13     0.29                                                  Verapamil      0.63     1.06                                                  ______________________________________                                    

From the data given in the table, it can be seen that some of thecompounds of the invention, such as compounds 4, 5, 6, 7 and 8, have ahypotensive activity similar to that of prazosin. The other tworeference compounds used, Verapamil and WB-1401, are less active.

4) Anti-hypertensive Activity in the Spontaneously Hypertensive (SHR)Rat

Some of the compounds of the invention were administered orally to theSHR rat with the use of various concentrations of product so as toenable the calculation of ED₂₀ values, that is, the dose in mg/kg whichcauses a 20% reduction in the mean basal systolic pressure 0-120 minafter administration. Animals having a mean basal systolic pressure ofnot less than 180 mmHg were used.

The values obtained in this way are shown in Table 6, which also givesthe maximum effect on blood pressure caused by the 3 mg/kg dose for eachproduct examined, as well as the effect of this dose on cardiacfrequency.

                  TABLE 6                                                         ______________________________________                                        Reduction in systolic arterial pressure in the                                spontaneously hypertensive (SHR) rat induced by                               the oral administration of the indicated                                      compounds of the invention                                                              Systolic pressure                                                                          Cardiac frequency                                                Max effect ED.sub.20 Max effect                                               at 3 mg/kg (0-120 min)                                                                             at 3 mg/kg                                     Compound  % vs basal (mg/kg)   % vs basal                                     ______________________________________                                        1         -7.5       NC.sup.1  -0.8                                           2         -6.4       NC        +2.1                                           4         -15.5      13.1      +0.6                                           5         -22.1      2.0       -0.2                                           6         -8.4       NC        +2.7                                           7         -22.7      2.2       +0.9                                           8         -20.2      2.6       -5.2                                           Prazosin  -20.0      2.8       +9.7.sup.2                                     Verapamil -9.0       NC        +2.8                                           WB-4101   -2.6       INACTIVE  -5.7                                           ______________________________________                                         Note:                                                                         .sup.(1) : NC: not calculable                                                 .sup.(2) : statistically significant (p < 0.05)                          

From the data given in the table, it can be inferred that many of thecompounds of the invention display a powerful anti-hypertensive actionin the spontaneously hypertensive rat.

Thus, for example, compounds 5, 7 and 8 are shown, in this experiment,to be about as powerful as prazosin, the reference alpha₁ -adrenergicantagonist. In addition, in the range of doses tested, 0.3-10 mg/kg, thecompounds of the invention do not appear to induce reflex tachycardia asa result of the reduction in pressure. However, prazosin, at the 3 mg/kgdose, produces a significant increase in frequency of approximately 10%over the basal frequency. Of the other two reference compounds tested,WB-4101 is inactive, probably because it is poorly absorbed by the oralroute, while the calcium antagonist, verapamil, is less effective inthat it does not reduce the arterial pressure by more than 9% at a doseof 3 mg/kg.

A further important and advantageous characteristic of the compounds ofthe invention is the high level of absorption that they show followingoral administration, and their long half-lives. This is shown clearly bythe data obtained with Compound 7, administered to the rat at 1 mg/kg IVand 15 mg/kg OS. These results are given in Table 7 below.

                                      TABLE 7                                     __________________________________________________________________________    Plasma concentration (μg/ml) of Compound 7 in                              the rat                                                                                                          AUC                                        Time (hours)                       (μg/ml-                                 0.083                                                                              0.25                                                                             0.5                                                                              1  2  3  4  6  8  12 24 hour)                                      __________________________________________________________________________    IV                                                                              0.42                                                                             0.30                                                                             0.18                                                                             0.10                                                                             0.04                                                                             0.02                                                                             0.01                                                                             0  -- -- -- 0.30                                       OS                                                                              -- 0.23                                                                             0.36                                                                             0.48                                                                             0.39                                                                             0.34                                                                             0.32                                                                             0.28                                                                             0.18                                                                             0.08                                                                             0.02                                                                             3.62                                       __________________________________________________________________________

From the data given it can be seen that the relative bioavailability ofCompound 7 (that is, the ratio AUC_(OS) /AUC_(IV)), allowing for thecorrections which are necessary to take account of the different dosesused for the two routes of administration, is extremely high(approximately 80%).

The half-life calculated for the terminal elimination phase is also high(approximately 6 hours); much greater therefore than that reported inthe literature for, for example, prazosin [approximately 2hours--Martindale--29th Ed.--page 496]. This result shows that this andother compounds of the invention can, to advantage, be administered tohumans in one or, at most, two daily doses.

We claim:
 1. A compound represented by the general formula (I) indicated below ##STR9## in which: Ar isan unsubstituted pyridyl group (2-, 3- or 4-yl) or a pyridyl group mono-substituted with a methoxy or methyl group an unsubstituted furyl group (2- or 3-yl) or a furyl group substituted with a methoxy or methyl group, or a benzofuryl group (2- or 3-yl)and its salts obtained from pharmaceutically acceptable inorganic or organic acids.
 2. A compound according to formula (I) of claim 1, in which Ar is an unsubstituted pyridyl group (2-, 3- or 4-yl) or a pyridyl group mono-substituted with a methoxy or methyl group, and its pharmaceutically acceptable salts.
 3. A Compound according to claim 2, in which Ar is the 2-pyridyl group, and its pharmaceutically acceptable salts.
 4. A compound according to formula (I) of claim 1, in which Ar is an unsubstituted furyl group (2- or 3-yl) or a furyl group substituted with a methoxy or methyl group, and its pharmaceutically acceptable salts.
 5. A compound according to claim 4, in which Ar is a 2-furyl group, and its pharmaceutically acceptable salts.
 6. A pharmaceutical preparation comprising, as an active ingredient, at least one of the compounds according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable inactive ingredient.
 7. A pharmaceutical preparation according to claim 6, wherein the pharmaceutically acceptable inactive ingredient is selected from the group consisting of vehicles, binders, aromatisers, dispersants, preservatives, humectants, and mixtures thereof, ingredients which facilitate transdermal absorption, and ingredients which enable the controlled release of the active ingredient over time.
 8. A method for treating arterial hypertension of diverse etiology comprising administering an effective amount of a pharmaceutical preparation according to claim 6 to a patient in need thereof.
 9. A method for treating prostate hypertrophy comprising administering an effective amount of a pharmaceutical preparation according to claim 6 to a patient in need thereof.
 10. A method for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, which comprises reacting a piperidine derivative of formula (II): ##STR10## in which Ar is defined in claim 1, with 2-Cl-4-amino-6,7-dimethoxy-quinazoline in a high boiling solvent, in the presence or absence of a tertiary base as a proton acceptor, at a temperature of 70-150° C. for 1-48 hours, and isolating a compound of formula (I) from the reaction medium by filtration either as such, or in the form of a pharmaceutically acceptable salt.
 11. A method according to claim 10, wherein said high boiling solvent is isoamyl alcohol.
 12. A method according to claim 10, wherein the compound of formula (I) is isolated in the form of its pharmaceutically acceptable salt. 